The field of the invention is the area of the testing of pharmaceuticals in animal model systems, particularly those pharmaceuticals of benefit in protecting a human or animal against oxidative damage.
Oxygen is a critical element in biological systems, having roles including a terminal electron acceptor in oxidative phosphorylation, in dioxygenase reactions, in hydroxylation reactions, in reactions involving activation and/or inactivation of xenobiotics, including carcinogens and in normal animal host defense mechanisms. Despite the wide range of essential and desirable reactions in which oxygen plays a role, the generation of excess amounts of oxygen free radicals through cellular processes has deleterious effects on biological systems including, without limitation, membrane lipid peroxidation, oxidation of nucleic acids, oxidation of sulfhydryl bonds and other moieties which are sensitive to oxidative damage. It has also been theorized that the effects of aging are due, in part, to cumulative oxidative damage to cellular systems.
Biological antioxidants include enzymes such as superoxide dismutase, catalase, selenium glutathione peroxidase and phospholipid glutathione peroxidase and compounds including tocopherols, tocotrienols, carotenoids, quinones, bilirubin, ascorbic acid, uric acid, ovothiols and certain metal binding proteins.
Oxygen free radicals in biological systems include superoxide anion (•O2 2−). Sequential univalent reactions of the superoxide radical yield hydrogen peroxide, hydroxyl radical, and water. Catalase converts hydrogen peroxide to water and molecular oxygen.
Oxygen radical injury has been implicated in pulmonary oxygen toxicity, adult respiratory distress syndrome, bronchopulmonary dysplasia, sepsis syndrome, amyotrophic lateral sclerosis, and various ischemia-reperfusion syndromes including myocardial infarction, stroke, cardiopulmonary bypass, organ transplantation, necrotizing enterocolitis, acute renal tubular necrosis, mitochondrial disease, Alzheimer's disease, and Parkinson's disease among others. Accumulated free radical damage has also been associated with the normal aging process.